Apart from conducting a long-term, placebo-controlled clinical trial involving tens of thousands of people, is there any way to ensure that a COVID-19 vaccine will work? Numerous researchers argue that the success of several vaccines that are now widely used demonstrates a shortcut: Simply put, the ability of a vaccine to elicit so-called neutralising antibodies, which bind to the virus and prevent it from entering cells, is measured.
However, several recent studies, the most recent of which was published as a preprint on 24 June, point to additional “correlates of protection”: “binding” antibodies—which bind to the virus but do not prevent entry—and another type of immune warrior known as T cells.
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Vaccine decisions may soon be contingent on a more complete understanding of these auxiliary actors. Several companies are updating their COVID-19 vaccines to protect against new viral variants, hoping that regulatory agencies will not require them to demonstrate efficacy in large clinical trials, which are not only time consuming and expensive, but also increasingly ethically fraught because some participants receive a placebo despite the availability of proven vaccines.
With a well-established correlate of protection, trials can administer an updated vaccine to a much smaller group of participants and then monitor for the requisite immune responses. (This is how annual flu vaccine updates are approved.) Correlations may also be used by health officials when deciding on the priority of existing COVID-19 vaccines, authorising new “mix and match” combinations, or even when developing entirely new vaccines.
However, establishing robust correlates has proven difficult. Throughout the megatrials that resulted in the approval of COVID-19 vaccines, investigators monitored antibody responses and attempted to correlate them with participants’ chances of becoming ill. However, different trials used different antibody assays and had varying definitions of mild COVID-19, the trial’s primary endpoint.
“It’s anarchy because it’s always been anarchy,” says John Moore, an immunologist at Weill Cornell Medicine.
“You’re dealing with different academic labs and different companies, and companies tend not to talk to each other.”
Numerous trials also lacked the statistical power to assess protection against hospitalization and death, arguably the most critical function of a COVID-19 vaccine. And few trials examined T cells in detail, which are far more difficult to quantify.
Nonetheless, two studies—first published as preprints in March here and here—confirmed Moore’s and numerous other scientists’ prediction that neutralising antibodies (“neuts”) play a critical role. To “normalize” the various assays used in the trials, they compared antibody levels elicited by each vaccine to antibody levels found in people who became infected naturally in the placebo group. Both analyses found that vaccines that induced higher levels of neuts than those typically seen in recovered individuals provided the best protection—strong evidence of a correlation, Moore says.
“That’s a great relief to me,” says Penny Moore, a virologist at the National Health Laboratory Service in South Africa, who helped measure protective immune responses in different vaccine trials and was “really puzzled” by the results.
However, she and others suspect that neuts are not the entire story.
“I just cannot work out for the life of me how much [other immune responses] are contributing and where they’re contributing,” she says.
For example, during efficacy trials for the messenger RNA (mRNA) vaccines developed by the Pfizer-BioNTech collaboration and Moderna, the first dose of both vaccines induced barely detectable levels of neutralizing antibodies but provided significant protection.
“It suggests there’s more than neutralizing antibodies going on here,” says David Montefiori, an immunologist at Duke University.
Neuts increased dramatically only after the second mRNA shot, when protection increased to more than 90%.
T cells appear to bolster the defence by not only coordinating B cells that produce antibodies but also clearing infected cells when neuts fail. In a study published in February, a team led by immunologist Antonio Bertoletti of the Duke–National University of Singapore Medical School reported that patients who had the highest levels of immune system messengers that activate T cells early on—an indirect, but relatively simple, way to measure their presence—had milder COVID-19.
Penny Moore and colleagues also discovered evidence for T cells playing a role. They reported in a June 11 preprint that 96% of participants in an efficacy trial of Johnson & Johnson’s (J&J) COVID-19 vaccine produced antibodies that neutralized an early pandemic viral strain, but only 19% produced antibodies that neutralized the Beta variant, which is prevalent in South Africa and infamous for evading neuts. Despite the variant, the vaccine remained protective against COVID-19 infection at moderate and severe levels.
“I think it’s entirely plausible … that T cells are doing something really useful here,” Penny Moore says.
A monkey study using this vaccine, published in Nature last year, also demonstrated that T cells contributed significantly to virus control when neut levels were insufficient to do the job.
Antibodies that bind to proteins may also be more important than previously assumed. According to the preprint published on June 24 by researchers at the University of Oxford, high levels of neuts were associated with an 80 percent protection achieved 28 days after participants in the United Kingdom received two shots of the vaccine developed by the team in collaboration with AstraZeneca. However, a closer examination of the data revealed that binding antibodies were just as good—if not better—as a correlate.
It is unknown why, as binding antibodies do not directly inhibit the infection process. One possibility is that they predispose the virus to being consumed by macrophages or other cells that consume intruders. In March, immunologist Galit Alter of the Ragon Institute of MGH, MIT, and Harvard reported in Nature Medicine that this mechanism, called phagocytosis, protected children from severe COVID-19 infection. However, binding antibodies may be produced in lockstep with neuts, but at a higher level, and thus serve as a surrogate marker.
In a study of 24 COVID-19 patients with disease ranging from mild to fatal, virologists Shane Crotty and Alessandro Sette of the La Jolla Institute for Immunology found that people handle SARS-CoV-2 best when their T cells and antibodies work together. “The immune system learns to use all its weapons,” Crotty says.
The pitfalls of overemphasising neuts have been demonstrated in South Africa, where less than 1% of the population is fully vaccinated. In February, the country abandoned the AstraZeneca-Oxford vaccine after a large trial revealed only 22% efficacy against mild disease. Antibodies generated by the vaccine had far less neutralizing power against the Beta variant, which accounted for nearly all infections. However, Penny Moore’s study of the J&J vaccine showed that low levels of neutralising antibodies don’t prevent a vaccine from protecting against severe disease.
“Our obsession with neuts may mean that we missed an opportunity here for AstraZeneca,” she says.
Others argue that using neuts to compare the efficacy of different vaccines makes sense, but that standardization is required. Chinese researchers published national SARS-CoV-2 neutralization assay standards in Vaccine on June 23.
“This has not been the most important priority, but it’s going to become one if we move away from phase 3 trials,” John Moore says.
Regulators must now decide whether correlates of protection should be used to speed up the development of new vaccines. Pfizer and Moderna are working on next-generation candidates that will generate high levels of neutralizing antibodies against Covid, and the FDA has indicated that it will consider this correlate of protection when approving drugs.
“Even though we might not get the perfect surrogate—it might mediate partial protection—that could be good enough,” says Peter Gilbert, a biostatistician who designs clinical trials at the Fred Hutchinson Cancer Research Center.
“We don’t need perfection here.”
In fact, Alter fears regulators will approve unnecessary booster shots simply because they outperform existing shots.
“If [regulators] don’t adapt, we’re going to end up overboosting, and we’re going to be making the drug companies really happy,” she says.
It’s also unclear whether a strong correlation from one vaccine platform (mRNA) applies to another (viral vector).
“We’re hoping to have more immune correlate of protection information before updates on that,” says Peter Marks, who heads FDA’s vaccine division.
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With more than a dozen vaccines in use now, Sette believes that information will be available soon. Although companies usually control clinical trial data, academic labs can now compare vaccine recipients, he says.
“In the next few months, all the different labs will be generating analyses of what different vaccines do and a large amount of data will be generated in academic labs,” Sette says.
“There’s going to be a fundamental wealth of information.”
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